Activated Ras as a Direct Therapeutic Target for Neurofibromatosis Type 1: An Innovative Approach for Identifying Classes of Inhibitors

Neurofibromatosis Type 1 NF1 arises from the aberrant activation of Ras, a GTPases important controlling mitogenic potential. In an effort to control the aberrant activation of Ras to treat NF1 as well as other cancer, a high throughput screen was developed to screen for small molecule inhibitors of Ras activation by Sos1, a ubiquitous guanine nucleotide exchange factor that catalyzes the activation of Ras. Using this screen, several initial leads have been identified. Future work will define the efficacy and modes of action of these compounds to inhibit Sos1-catalyzed activation of Ras prior to more extensive quantitative structure-activity relationships.